Kinetic resolution of a intermediate useful in the production of benazepril and analogues thereof

ABSTRACT

The present invention provides an efficient synthetic process for making benazepril and analogues thereof by having an intermediate compound undergo epimerization and kinetic resolution.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This application is a Continuation-in-Part of U.S. patentapplication Ser. No. 09/910,509, filed Jul. 19, 2001, which claimspriority from a Provisional Patent Application filed in U.S.A. on May18, 2001, No. 60/291,888. The disclosures of U.S. patent applicationSer. No. 09/910,509 and Provisional Patent Application No. 60/291,888are incorporated herein by reference.

[0003] The present invention relates to a process for the preparation ofan angiotensin-converting enzyme (ACE) inhibitor useful in the treatmentof hypertension, chronic heart failure and progressive chronic renalinsufficiency. In particular, the processes of the present invention areuseful for the commercial production of3-[(1′-(alkoxycarbonyl)-3′-phenylpropyl)amino-2-oxo-[1]-benzazepine andderivatives thereof. More notably, the present invention demonstrates anunique process of converting an intermediate compound in the synthesisof benazepril from one diastereomer form R,S to another diastereomerform S,S, which is the desired form for the production of benazepril byutilizing a process of epimerization and kinetic resolution of a classof chemical compounds.

[0004] 2. Description of the Related Art

[0005] One of the most popular ACE inhibitors is benazepril,3-[(1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-10(3S)-benzazepine-1-aceticacid, which has a general formula as shown below and is generallymarketed as the mono hydrochloride form (benazepril HCl) andadministered orally in therapeutic use.

[0006] A number of previous publications and patents have disclosedprocesses for the preparation of benazepril, including HelveticaChimnica Acta (page 337, vol. 71, 1988), Journal of the ChemicalSociety: Perkin Transaction I (page 1011, 1986), U.S. Pat. Nos.4,410,520 (1983), 4,473,575 (1984), 4,575,503 (1986), 4,600,534 (1986),4,785,089 (1988), 5,066,801 (1991), and 5,098,841 (1992)

[0007] Prior methods employ sulfonate esters of 2-(R)-hydroxy-4-phenylbutonate alkyl esters condensing with 3-(S)-amino-ε-caprolactam for thesynthesis of benazepril. However, the use of sulfonate esters requires achiral 2-(R)-hydroxy-4-phenyl butanate alkyl ester and an expensiveleaving group in the form of a substituted phenyl sulfonate ester.Additionally, the reaction can sometimes lead to undesirableracemization.

[0008] U.S. Pat. Nos 4,410,520 and 4,575,503 disclose processes for thepreparation of 3-amino-[1]-benzazepin-2-one-1-alkanoic acids. Theprocesses are complex by either first bonding a chiral amino group tothe 1-position carbonyl group, or by attaching a chiral amino group tothe 3-position carbon with a good leaving group through a two-stepreaction. Consequently, the processes require several complex reactionsteps, which may be more costly to conduct.

[0009] A simpler and more efficient process for preparing3-[(1′-(alkoxycarbonyl)-3′-phenylpropyl)amino]-2-oxo-[1]-benzazepin-(1-alkylacids) is desirable. The present invention discloses a process ofdirectly bonding a chiral amino acid ester to the 3-position carbon of2,3,4,5,-tetrahydro-1H-1-benzazepine-2-one derivatives to produce amixture of diastereomers, and a novel epimerization process andresolution process to convert the undesired diastereomer form, R,S, intothe desired diastereomer form S,S in high yield. The production of theS,S form of benazepril is thus greatly simplified.

[0010] For certain chemical compounds when used as therapeutic drugs,only one specific stereoisomer is effective. The other stereoisomers ofthe same compound may be less effective or have no effect at all. As ageneral technique, kinetic resolution (crystallization duringepimerization) has been used to stereoselectively produce a singlediastereomer from a mixture, see Marianne Langston, et. al, OrganicProcess Research & Development, 4:530-533 (2000). The success of thismethod depends on a large solubility difference between thediastereomers and a condition that facilitates effective epimerizationof the desired optical center. Thus, in a predetermined solvent, thedesired diastereomer should have low solubility and thus precipitateeasily while the undesired diastereomer has a higher solubility and thusremains in the solution. As the desired diastereomer forms crystals, itsconcentration in the solution becomes lower, a condition that helpsfurther conversion from the undesired diastereomer to the desired one.

[0011] The synthesis of benazepril, an important angiotensin convertingenzyme (ACE) inhibitor, is made difficult due to the need to prepare theS,S diastereomeric form of the compound. The need to chemically resolvean early intermediate or to chemically synthesize a chiral intermediateadds much more expense to the synthesis. For example, NovartisPharmaceuticals reported a process for the production of the (S)-chiralamine form based on a crystallization technique. While this methodproduced good yields of the desired s-chiral amine form, the necessarystep of subsequently producing the (S)-homophenyl alanine portion isvery expensive. In addition, the expensive S-phenylethyl amine used inthe process is completely lost during the processing, further increasingthe costs. It would be much more desirable if the S-homophenyl alaninecould be coupled with the benzlactam portion without racemization andthen the desired (S) chirality could be induced at the site alpha to thelactam. These steps are demonstrated in the present invention.

BRIEF DESCRIPTION OF THE FIGURES

[0012] Scheme 1 schematically illustrates the present invention ofcoupling the S-homophenyl alanine with the benzlactam and the resolutionof the two diastereomers which are formed through an epimerization,kinetic resolution step to greatly increase the amount of the desiredS,S form.

[0013] Scheme 2 illustrates the conversion of(1′S,3S)-3-[(1′-(ethoxycarbonyl)-3′-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepineto benazepril hydrochloride, an angiotensin-converting enzyme (ACE)inhibitor.

SUMMARY OF THE INVENTION

[0014] One object of the present invention is to demonstrate anefficient process for the preparation of3-[(S)-1′-(alkoxycarbonyl)-3′-phenylpropyl)amino]-2-oxo-[1]-benzazepineand derivatives thereof. A compound of the formula (III) can be preparedby the reaction of a compound of the formula (I) with a compound of theformula (II), where R₂ is a lower alkyl such as ethyl, proplyl andbutyl, under basic conditions in the presence of a phase transfercatalysis in an aprotic polar solvent. The reaction can be furthercatalyzed by addition of alkali metal halides such as sodium orpotassium iodide.

[0015] where Z₁=halide such as Br, Cl and I

[0016] Where

[0017] R₁=hydrogen, lower alkyl or a combination of hydrogen and alkylgroups

[0018] R₂=a lower alkyl group having 1 to 4 carbon atoms

[0019] Z₂=halide such as Br, Cl and I

[0020] In a preferred embodiment, compound of formula (II) isS-homophenylalanine alkyll ester. When S-homophenylalanine alkyll esteris optically pure, the chiral center at the 2-position can be reactedwith the compound of formula (I) without racemization to form goodyields of compound (III).

[0021] The initial products obtained by the method disclosed therein istherefore a pure mixture of only two diastereomers (hereinafter“S,S/R,S”)

[0022] By a conventional method, i.e., through simple crystallization,the desired S,S form can be separated. However, a low yield of onlyapproximately 30% is obtained and thus, about 70% of this expensivematerial would be wasted. It is desired to have a method to recycle thematerial back to the crystallization. This requires a method toselectively epimerize just the center alpha to the lactam without lossof chirality in the sensitive S-homophenylalanine moiety. Becauseremoval and thus epimerization of the S-homophenylalanine ester protonwas shown to be more facile under all conditions explored, we desired amethod to accomplish this epimerization in high yield and opticalpurity. The present invention provides such a method to selectivelyepimerize the undesired R,S forms to the desired (R,S),S diastereomericmixture which can then be reused in the crystallization process. Also,surprisingly, the present invention demonstrates a method for the directconversion of the R,S form to the desired S,S form by kinetic resolutionwhich eliminates the need to recycle the intermediate. This isillustrated schematically in scheme 1 and discussed below.

[0023] An economic process is complicated by the fact that the chiralposition on the homophenyl alanine ester is more labile than thebenzlactam chiral position under a variety of epimerization conditions.Epimerization occurring on the wrong position would complete destroy theability to recycle the material. The applicant discovered, however, thatan initial conversion of the ester to a carboxylic acid could achievetwo desired effects of: (1) deactivating epimerization at the wrongposition, i.e., the chiral position on the homophenyl alanine and (2)inducing reaction at the desired position, i.e., the benzlactam chiralposition. Thus the R,S diasteriomer of the carboxylic acid compoundundergoes an epimerization process under basic or neutral conditionresulting in a mixture RS,S diastereomers resulting from the selectiveepimerization at the lactam position. Furthermore, by careful choice ofepimerization and crystallization conditions, a kinetic resolution canbe made to occur during which the R,S diasteriomer is converted in highyield directly to the desired S,S diasteriomer. Once the R,S carboxylicacid compound is converted predominantly to the S,S diastereomer, it isconverted back to the ester compound without loss of chirality byesterification.

[0024] The above described epimerization and kinetic resolution can beachieved under a variety of conditions provided that the desired S,Sdiastereomer is less soluble in the media. The best results are obtainedwith the free acid, rather than the acid salts. The epimerization can bemade to occur thermally and therefore requires a sufficiently hightemperature. The high temperature condition can be achieved by eitherusing a high boiling solvent or by heating the reaction mixture underpressure to increase its boiling temperature. Good results can beachieved in both polar and non-polar solvent systems, as long as thesolubility and thermal requirements are met. For example, both xyleneand ethylene glycol-water systems are found suitable to conduct theepimerization and chiral induction process. Propionic acid and aceticacid may also be used to conduct the epimerization and chiral inductionprocess. While it is apparent that the process can take place in avariety of solvent systems, aromatic hydrocarbons such as xylene are thepreferred solvent. Temperatures between 25° C. and 150° C. are indicatedwith higher temperatures necessary in the more non-polar solvents. Theresults of the epimerization or racemisation studies using variousorganic solvents are shown in the examples.

[0025] The carboxylic acid compound can be converted to the desiredethyl ester compound by re-esterification without loss of chirality. Theesterification can be carried out in a number of ways known to thoseskilled in the art, but the preferred method is by reacting with ethylbromide and potassium carbonate in a polar solvent such asdimethylacetamide.

[0026] The invention will be more specifically understood in terms ofthe following example, which is exemplary only and do not limit thescope of the invention.

EXAMPLES Example 1

[0027] Step (a)

[0028] 3-Bromo-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (17.68 g) wasprepared by a method analogous to that given in Helvetica Chimica Acta(page 337, vol. 71, 1988). L-homophenylalanine ethyl ester (L-HPAEE,19.91 g) was prepared, by-extracting hydrogen chloride salt ofL-homophenylalanine ethyl ester (L-HPAE, HCl, 30 g) with ethyl acetatein a solution of sodium carbonate (15 g Na₂CO₃ in 100 ml H₂O).

[0029] Sodium bicarbonate (6.84 g), tetra-n-butylammonium bromide (TBAB,1.191 g), 3-bromo-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (17.68 g),and N,N-dimethylacetamide (40 ml) were subsequently added to a flaskunder nitrogen. L-HPAEE was mixed with N,N-dimethylacetamide (30 ml) andthe mixture was then added to the flask. The mixture was stirred andheated to 110° C. for 6 hours. At this temperature sodium bicarbonate isconverted mainly to sodium carbonate.

[0030] The mixture was further extracted and analyzed by high pressureliquid chromatography (HPLC) and the results showed that 39.5% of(1′S,3S)-3-[(1′-(ethoxycarbonyl)-3′-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepineand 40.31% of(1′S,3R)-3-[(1′-(ethoxycarbonyl)-3′-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine.The desired S,S form of the product could be crystallized out usingsolvents of ethyl acetate and heptane in the yield from 25% to 33%.

Example 2

[0031] The procedure of Example A was repeated, except that sodiumiodide (0.96 g) was added to enhance reaction rates in exchanginghalogens and to reduce the amount of by-products. The results showedthat the mixture contained 40.7% of(1′S,3S)-3-[(1′-(ethoxycarbonyl)-3′-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepineand 41.4% of(1′S,3R)-3-[(1′-(ethoxycarbonyl)-3′-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine.

Example 3(1′S,3R,S)-3-[(1′-carboxyl-3′-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine(IV)

[0032](1′S,3R,S)-3-[(1′-carboxyl-3′-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzapineethyl ester (III) (2.47 kg) was dissolved in 1 liter of methanol.Subsequently, 3N aqueous NaOH (2.4L) was added to reaction mixture andthe mixture was stirred for 2 hours at 40-50° C. The slurry was cooledand 2 N hydrochloric acid (3436 ml) was added to acidify the solution.Methanol was removed by distillation to produce a solid which wasfiltered, washed with water and dried at reduced pressure to give 1.86kg of the crude acid (IV).

Example 4(1′S,3,S)-3-[(1′-carboxyl-3′-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine(V)

[0033] Xylene (30L) was added to 1.86 kg of compound IV. The slurry washeated at 150-155° C. for 8 hours under approximately 1.5 atm pressure.The reaction mixture was cooled to room temperature. The solid wascollected by filtration and dried at reduced pressure to yield 1.67 kgof (S,S) diasteriomer (V) as a 98:2 S,S:R,S diasteriomeric mixture asdetermined by HPLC. The ratio of enantiomers as determined by HPLC isS,S:R,R=93:7 and the chemical yield was 92%. The compound wascharacterized as follows: mp 287-290° C.; ¹HNMR (DMSO, 400 MHz)d1.63-1.82(m, 2H), 1.88-2.04(m, 1H), 2.31-2.42(m, 1H), 2.50-2.80(m, 4H),3.01 (t, J=6.2 Hz, 1H), 3.15(dd, J=7.8, 11.0 Hz, 1H), 4.02(br, 1H),6.96(d, J=7.6 Hz, 1H), 7.08-7.16(m, 4H), 7.18-7.31(m, 4H), 9.88(s, 1H)

Example 5

[0034] In a similar manner to example 4, xylene (2.76L) was added tocompound IV (83 g). The slurry was heated to 138-143° C. and maintainedat this temperature for 3 hours. After this period, the mixture wascooled to room temperature. The solid was collected by filtration anddried under reduced pressure to give 74.7 g of compound V (S,S) as a97:03 diasteriomeric mixture as determined by HPLC. The ratio ofenantiomers as determined by HPLC is SS:RR=95:05 and the yield is 86%.

Example 6

[0035] In a similar manner to example 4, propionic acid (12 ml) wasadded to compound IV (2 g). The slurry was stirred at 60° C. for 30minutes. After this period, the reaction mixture was cooled to 25° C.The solid was collected by filtration, washed with ethyl acetate anddried at reduced pressure to give 1.5 g of compound V as a 70:30diasteriomeric mixture as determined by HPLC. The ratio of enantiomersas determined by HPLC is SS: RR=86:14 and the yield is 75%.

Example 7

[0036] In a similar manner to example 4, acetic acid (6 ml) was added tocompound IV (1 g). The slurry was stirred at room temperature for 1 hr.The solid was collected by filtration, washed with ethyl acetate anddried at reduced pressure to give 0.7 g of compound V as a 99:1diasteriomeric mixture as determined by HPLC. The ratio of enantiomersas determined by HPLC is SS: RR=85:15 and the yield is 70%.

Example 8

[0037] In a similar manner to example 4, ethylene glycol (9 ml) and H20(1 ml) were added to compound IV (1 g). The slurry was heated to 138° C.and stirred at this temperature for 3.5 hr. After this period, thereaction mixture was cooled to 25° C. The solid was collected byfiltration, washed with ethyl acetate and dried under reduced pressureto give 0.83 g of compound V as a 99:01 diasteriomeric mixture asdetermined by HPLC. The ratio of enantiomers determined by HPLC is SS:RR=81:19 and the yield is 83%.

Example 9

[0038](1′S,3R)-3-[(1′-carboxyl-3′-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine(100 mg) and THF (5 mL) were mixed and cooled to 0° C. Then the CH3ONa(30 mg) was added to the reaction mixture. Then the reaction temperaturewas kept at 25° C. for one hour. The pH was adjusted to 2.5 to 2.0 by 3NHCl solution. The solid was filtered off and dried at reduced pressureto give 93 mg of compound (IV) as a 54:46 S,S:R,S diasteriomeric mixtureas determined by HPLC.

Example 10(1′S,3S)-3-[(1′-(ethoxycarbonyl)-3′-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine(VI)

[0039] Compound V (450 g), N,N-dimethylacetylamide (2L), bromoethane(115 ml), and potassium carbonate (65 g) were added to the reactionflask. The reaction mixture heated to 60-70° C. and was stirred for 2hours at this temperature. The mixture was cooled and 3.5 L of water wasadded to the mixture at 10° C. The resulting precipitate was collectedby filtration, washed with an additional 2L of water and dried atreduced pressure to give 520 g of crude solid. This solid was dissolvedin a mixture of 0.6L of ethyl acetate and 1.2L of Heptanes at 40-50° C.The solution was cooled to 30° C. and the product was isolated byfiltration to obtain 390 g of VI (S,S) as a >99:1 diasteriomeric mixtureas determined by HPLC. The ratio of enantiomers determined by HPLC isSS:RR>99.5:0.5. and the yield is 80%. The compound is characterized asfollows: mp 119-120° C.; [α]²⁰-204° (c=0.99, EtOH), IR(KBr): 3250, 1726,1671 cm-1; 1HNMR (CDCl3, 400 MHz) d 1.14(t, J=7.2 Hz, 3H), 1.91-2.07(m,3H), 2.43-2.53(m, 2H), 2.59-2.64(m, 2H), 2.68-2.75(m,2H), 2.82-2.92(m,1H), 3.25-3.35(m, 2H), 4.01-4.11(m, 2H), 6.95-7.04(m, 1H), 7.10-7.29(m,8H), 8.64-8.80(br s, 1H); 13CNMR (CDCl3, 50 MHz) d 14.1, 28.8, 32.0,35.0, 37.8, 56.6, 60.0, 60.5, 122.0, 125.8, 125.9, 127.5, 128.2, 129.5,134.3, 136.5, 141.3, 174.2, 175.2; HRMS, Cal. For C₂₂H₂₆O₃N₂:366.1945(M+), found: 366.1950(M+)

[0040] The invention is not limited by the embodiments described abovewhich are presented as examples only but can be modified in various wayswithin the scope of protection defined by the appended patent claims.

[0041] Thus, while there have shown and described and pointed outfundamental novel features of the invention as applied to a preferredembodiment thereof, it will be understood that various omissions andsubstitutions and changes in the form and details of the devicesillustrated, and in their operation, may be made by those skilled in theart without departing from the spirit of the invention. For example, itis expressly intended that all combinations of those elements and/ormethod steps which perform substantially the same function insubstantially the same way to achieve the same results are within thescope of the invention. Moreover, it should be recognized that theelements and/or method steps shown and/or described in connection withany disclosed form or embodiment of the invention may be incorporated inany other disclosed or described or suggested form or embodiment as ageneral matter of design choice. It is the intention, therefore, to belimited only as indicated by the scope of the claims appended hereto.All references cited herein are incorporated by reference in theirentirety.

We claim:
 1. A process for the preparation of a compound of the formula(III)

comprising the steps of reacting a compound of the formula (I)

wherein Z1 is a halogen, with a compound of the formula (II)

where R₁ hydrogen, lower alkyl or a combination of hydrogen and alkylgroup; R₂ is a lower alkyl group having 1 to 4 carbon atoms; and Z₂ is ahalogen; in an aprotic polar solvent catalyzed by a phase transfercatalyst.
 2. The process of claim 1, wherein the phase transfer catalystis selected from the group consisting of tetra-alkylammonium halides,N-dodecyl-N-methyl-ephedrinium halides, phenyltrimethylammonium halides,phenyltrimethylammonium methosulfate, benzyltrimethylammonium halides,N-benzylcinchoninium halides, benzyldimethyldodecylammonium halides andbenzethonium halides.
 3. The process of claim 1, wherein the reaction isfurther catalyzed by an alkali earth metal halide salt.
 4. The processof claim 3 wherein the salt is sodium iodide or lithium iodide.
 5. Theprocess of the claim 1, wherein the reaction is carried out under basiccondition.
 6. The process of claim 5 where the basic condition isprovided by adding a base selected from the group consisting of sodiumbicarbonate, sodium carbonate, potassium bicarbonate, potassiumcarbonate, and lithium carbonate, and barium carbonate.
 7. The processof the claim 1 wherein the reaction temperature is between 60° C. and140° C.
 8. A compound of the formula (IV)


9. A process for making a carboxylic acid of the formula (V) comprisingepimerizing IV(R,S) in a solution comprising a polar or non-polarsolvent to a compound V where R₁ and R₂ are independently H, benzyl,alkylsilyl or carbamate


10. The process of claim 9 wherein the epimerization is done by heatingthe solution.
 11. A process of claim 9 in which R₁=H, R₂=H, andepimerization occurs by heating the solution.
 12. A process of claim 11in which the solvent is an alcohol, organic acid or aromatichydrocarbon.
 13. A process of claim 9 in which R₁=H, R₂=H and a base isused to epimerize IV(R,S).
 14. The process of claim 13 wherein the baseis selected from the group consisting of alkoxide, hydroxide, carbonateand amine.
 15. A process of claim 14 in which R₁=H, R₂=H, the base issodium methoxide, and the solvent is methanol.
 16. The process of claim9, further comprising selectively precipitating the compound of formulaV during epimerzation.
 17. The process of claim 16 in which theepimerization occurs by heating the solution.
 18. The process of claim17 in which the solvent is an aromatic hydrocarbon or an organic acid.19. The process of claim 18 wherein the organic acid is acetic acid orpropionic acid.
 20. The process of claim 18 in which the organic solventis xylene and the temperature for epimerization is greater than 120° C.21. The process of claim 9 wherein the carboxylic acid of formula V isconverted to an alkyl ester by esterification.
 22. The process of claim21 in which the esterification is effected with an alkyl halide andpotassium or sodium carbonate in a organic solvent.
 23. A process ofclaim 22 in which the organic solvent is dimethylacetamide.